To provide an initial step toward the understanding of the functional relationship between the onc genes of transforming retroviruses and their cellular prototypes, structural comparisons at the nucleic acid and protein levels have been carried out. We have determined the complete nucleotide sequence of the chicken ets gen and compared it to the ets gene of E26. E26 is a genetic hybrid with equences derived from viral structural genes and parts of essential cellular prot-onc genes. The cellular genes contain additional 5' sequences. The substitution of viral genes for parts of the normal cellular genes may be the most significant difference between these genes, perhaps eliciting functional differences between their gene products. The avian cellular gene transcript is considerably larger than the amount of DNA trnsduced by the virus. We have determined that the mammalian homologues of v-ets consist of two distinct domains located on different chromosomes. Using chromosome-specific probes, we have shown that both loci (ets-1 and ets-2) are transcriptionally active, producing mRNA species. The sequences homologous to ets-1 and ets-2 are colinear in chicken proto-ets and have possibly become separate and functionally distinct since before the evolutionary divergence of Mammalia. The mammalian ets genes from man and mouse encode for essentially identical amino acids, and are over 90% conserved relative to the chicken ets gene. We have utilized synthetic peptides and bacterially-expressed proteins to elicit production of antibodies which specifically immunoprecipitate ets protein. DNA from human cell lines and tumors has been analyzed for polymorphism and/or gene rearrangement. Both ets-1 and ets-2 genes translocate from their normal position in cells presenting 11q23 and 22q22 rearrangements.